Adherence to international guidelines for the management of Helicobacter pylori infection among gastroenterologists and gastroenterology fellows in Italy: A Survey of the Italian Federation of Digestive Diseases ‐ FISMAD

Abstract Background Information on the management of Helicobacter (H.) pylori infection by gastroenterologists and gastroenterology fellows are scarce. We aimed to assess practice of gastroenterologists and gastroenterology fellows and their adherence to guidelines for diagnosis and treatment of H. pylori infection in Italy. Materials and Methods All gastroenterologists and gastroenterology fellows attending the National Congress of Digestive Diseases ‐ FISMAD were invited to fill‐in an on‐line questionnaire. The questionnaire included questions on the diagnosis and treatment of H. pylori infection. Results A total of 279 gastroenterologists and 61 gastroenterology fellows participated to the study. The 13C‐urea breath test was the most preferred method among gastroenterologists and fellows for the diagnosis of H. pylori infection (40.4% and 57.6%, respectively) and the confirmation of eradication (61.3% and 70%, respectively). Sequential therapy was the most preferred first‐line treatment of H. pylori for both gastroenterologists and gastroenterology fellows (31.8% and 44%, respectively), followed by bismuth quadruple therapy (31% and 27.6%, respectively) and clarithromycin triple therapy (26.8% and 22.4%, respectively). Only 30% of gastroenterologists and 38.5% of fellows used the clarithromycin triple therapy for the recommended duration of 14 days. Bismuth quadruple therapy was the most preferred second‐line therapy for both gastroenterologists and fellows. The majority of gastroenterologists and fellows would prefer an empirical therapy at third line (72.6% and 62.5%, respectively) and a susceptibility‐guided therapy at fourth line (46.7% and 71.4%, respectively). Conclusions Practices of gastroenterologists and gastroenterology fellows are in line with guidelines’ recommendations, apart for the first‐line treatment of H. pylori infection. Targeted educational interventions to improve adherence to guidelines are needed.


| INTRODUC TI ON
Although the prevalence of Helicobacter (H.) pylori infection has been decreasing over the last decades, this bacterium still infects more than half of the world's population. 1 H. pylori infection causes chronic gastritis, peptic ulcer and gastric malignancies, and it is also an organic cause of dyspepsia and extra-gastric diseases. [2][3][4] Thus, all patients testing positive for H. pylori should be offered an eradication therapy. 5 The management of H. pylori infection still represents an issue in clinical practice. The use of culture or molecular test to assess antibiotic susceptibility of H. pylori, the treatment to prescribe, and the test to confirm eradication are still debated. In particular, the eradication of H. pylori is becoming more difficult due to the increasing prevalence of antibiotic resistance, [6][7][8] and a number of antimicrobial regimens are now recommended.
Recent international guidelines by three separate authoritative groups from Europe, America and Canada provided evidence-based recommendations to help physicians in the diagnosis and treatment of H. pylori infection, [9][10][11] and a recent review reconciling guidelines showed a substantial agreement among guidelines' recommendations. 12 Currently, the 13 C-urea breath test (UBT) is considered the best method for both the diagnosis of H. pylori and the confirmation of eradication; testing for eradication should be performed at least 1 month after the end of therapy. 9 As for the treatment, a 14-day clarithromycin triple therapy is suggested only in patients who are from regions with a low prevalence (<15%) of clarithromycin resistance, whereas bismuth and non-bismuth quadruple therapies are mandatory in settings of high (15%) or unknown clarithromycin resistance. [9][10][11] Since few years, the new formulation of single-capsule bismuth quadruple therapy is available in many countries, including Italy. 13 Gastroenterologists play an important role in the management of H. pylori infection both in treating patients and in the guidance of practitioners. However, information on the practice of gastroenterologists in the diagnosis and treatment of H. pylori infection and their adherence to guideline recommendations is scarce.

A recent study reported that treatment of H. pylori infection by
European gastroenterologists is discrepant with current recommendation. 14 Similarly, a survey carried out in China showed among clinicians, of whom 85% were gastroenterologists, a gap between real-world practices and guidelines for the management of H. pylori infection. 15 In addition, there is consistent evidence that compliance of also primary care physicians with H. pylori guidelines is low. [16][17][18] It has been suggested that the poor practice of primary care physicians may be a further, albeit indirect, evidence of the suboptimal management of H. pylori infection by gastroenterologists. 19 Further information on the adherence of gastroenterologists to guidelines recommendations are needed in order to optimize the management of H. pylori infection in clinical practice. In addition, such information could inform scientific societies on the need for targeted educational interventions, that may be effective in increasing knowledge and compliance with H. pylori guidelines. 20 The aim of this study was to assess practice patterns of gastroenterologists and gastroenterology fellows and their adherence to international guidelines for the diagnosis and treatment of H. pylori infection in Italy. There were no incentives for the participation in the study. This study was an initiative of the Scientific Committee of FISMAD and was conducted after approval by the Governing Council of the Federation itself. Written informed consent to anonymous use of data provided in the questionnaire was individually obtained from all participating physicians.

| Questionnaire
The questionnaire was developed according to the available international guideline recommendations on the management of H. pylori infection. [9][10][11] The questionnaire had three sections, including a total of 16 multiple-choice questions. The first section contained five ques-

| Statistical analysis
We performed descriptive analyses using percentages for categorical variables. We calculated statistical differences between percentages using the Chi-square test or Fisher's test when appropriate.
A p value < .05 was considered statistically significant. Statistical analysis was performed using STATA version 16 (Stata Corp, College Station, Texas, USA).

| Study sample
A total of 534 gastroenterologists and 140 gastroenterology fellows were eligible for the study. Of these, 279 (52.2%) gastroenterologists and 61 (43.6%) fellows completed the questionnaire. Not all participants answered to all the questions, thus the number of responses for each question varied accordingly. The majority of gastroenterologists (62.3%) practiced in community hospitals, whereas 25.2% worked in teaching hospitals and 11.9% in private hospitals; as expected, the majority (85.3%) of gastroenterology fellows practiced in teaching hospitals. Gastroenterologists who participated to the study were similar to non-participants in terms of gender, area of residence and hospital setting, but were significantly older (p = .02), whereas no difference was found between participant and nonparticipant gastroenterology fellows. Table 1 shows demographic and professional characteristics of gastroenterologists and gastroenterology fellows.

| Diagnosis of H. pylori infection
The most preferred test for the diagnosis of H. pylori infection among gastroenterologists and fellows was UBT (40.4% and 57.6%, respectively), followed by stool antigen test (SAT) (32.1% and 30.5%, respectively). The majority of gastroenterologists (61.3%) and fellows (70%) would prefer UBT for the confirmation of H. pylori eradication.
Almost all gastroenterologists (85.3%) and fellows (88.3%) correctly prescribed a test for H. pylori eradication at least 4 weeks after the end of treatment.
Unfortunately, culture or molecular tests to assess antimicrobial susceptibility of H. pylori were available for only one third of gastroenterologists (33.7%). A significant higher proportion of fellows referred that such tests were available in their hospital (75%, p < .001). Table 2 shows practice patterns of gastroenterologists and gastroenterology fellows in the diagnosis of H. pylori infection.

| Treatment of H. pylori infection
Nearly half of gastroenterologists (45%) reported that less than 50% of their patients with H. pylori infection were naïve to treatment, which means that they treated more often patients with previous eradication failures. No significant difference was found with gastroenterology fellows.
About half of gastroenterologists (59%) and fellows (52.5%) reported that local prevalence of clarithromycin resistance was ≥15%, whereas for 18% of gastroenterologists and 11.9% of fellows was <15%; the prevalence of clarithromycin resistance was unknown for  After failure of second-line therapy, the majority of gastroenterologists (72.6%) and fellows (62.5%) still preferred an empirical rather than susceptibility-guided therapy. Either single-capsule bismuth quadruple therapy or levofloxacin triple therapy, if not already used, was the most frequent third-line therapy for both gastroenterologists (49.8%) and fellows (37.5%).
Only after failure of third-line therapy, the most preferred strategy was a susceptibility-guided therapy based on culture or molecular test; this approach was significantly more frequent among fellows than gastroenterologists (71.4% vs. 46.7%, p < .0001). Table 3 shows practice patterns of gastroenterologists and gastroenterology fellows in the treatment of H. pylori infection.

| Management of H. pylori according to the hospital setting
Compared with community hospitals, a significant higher proportion of physicians in teaching hospitals used UBT for confirmation of H. pylori eradication (69.8% vs. 56.3%, p = .02). Culture and genetic tests to assess H. pylori susceptibility were more frequently available in teaching than community hospitals (61.2% vs. 33.1%, respectively, p < .00001). This would partially explain the previous finding that antimicrobial susceptibility tests were more available for fellows than gastroenterologists, as fellows practiced in teaching hospitals more than gastroenterologists (85.3% vs. 25.2%, respectively p < .0001) ( Table 4).
There were no significant differences between teaching and community hospitals for the treatment of H. pylori infection, apart from a higher proportion of physicians in teaching hospitals who preferred a concomitant therapy at first line (10.5% vs. 3.5%, respectively, p = .03). After failure of three lines of treatment, more physicians in teaching than community hospitals preferred a susceptibility-guided therapy (63.4% vs. 45.2%, respectively, p = .003) ( Table 5).

TA B L E 2 Diagnosis of H. pylori infection
There is evidence that a previous course of clarithromycin and quinolone is associated with an increased risk of antibiotic resistance of H. pylori to that antimicrobial agent, 25 that will consequently impact on the outcome of eradication treatment. 26 Thus, guidelines recommend to investigate the previous use of antibiotics in order to derive an individual-based information on likely antimicrobial resistance of H. pylori. 9 This approach may be useful for the choice of the best therapy, in particular in areas of low or unknown clarithromycin resistance. Accordingly, we found that almost all gastroenterologists and fellows investigated a previous use of macrolides or quinolones before prescribing an eradication therapy.

Current guidelines advocate that the choice of the first-line
H. pylori eradication therapy should be based on the knowledge of the regional prevalence of clarithromycin antibiotic resistance. [9][10][11] For about 60% of gastroenterologists, the regional prevalence of Italy. 14 Sequential therapy, which is a 5-day amoxicillin-containing double therapy followed by a 5-day clarithromycin triple therapy, was initially designed to overcome the issue of clarithromycin resistance. Unfortunately, sequential regimen is undermined by single and, especially, dual resistance to clarithromycin and metronidazole. 29,30 Eradication rates with sequential therapy are consistently lower than that of concomitant o bismuth quadruple therapy. 14,31,32 Based on these data, all international guidelines have discouraged the use of sequential therapy in clinical practice. that only about one third of participants who preferred a clarithromycin triple therapy prescribed a 14-day regimen. A Cochrane meta-analysis showed that the optimal duration of triple therapy is 14 days, which is now the recommended treatment duration of clarithromycin triple therapy. 36 Unfortunately, the use of triple therapy for less than 14 days is still common among gastroenterologists in the eradication of H. pylori. 36,37 Single-capsule bismuth quadruple therapy was the most preferred second-line therapy by gastroenterologists, followed by levofloxacin triple therapy, which is in agreement with international recommendations. [9][10][11]

TA B L E 5 (Continued)
sequential therapy is the most preferred first-line therapy, whereas bismuth and non-bismuth quadruple therapies are still underused.
A minority of gastroenterologists and fellows would prefer clarithromycin triple therapy, but only one third uses the recommended 14-day regimen. Unfortunately, this is a cause of high rate of eradi-

CO N FLI C T O F I NTE R E S T
The authors have no conflict of interest to declare.

AUTH O R CO NTR I B UTI O N S
RMZ and FB conceived the study and drafted the protocol. RMZ, MR, and LF performed statistical analysis and drafted the manuscript. All the other authors revised the manuscript and approved the final version.